The HIV pandemic continues unabated. In most HIV-infected persons, chronic infection is associated with weak effector anti-HIV T cell responses, but the molecular basis for such impaired T cell responses are still largely unknown. Studies of the mechanisms underlying defective immune control of HIV infection are still critically needed for the development of novel therapeutic strategies. The crucial role of natural regulatory T cells (Treg), a specialized subset of CD4+ T cells, in defective immune control of HIV infection has been proposed, based on the fact that the depletion of Treg from the peripheral blood mononuclear cells from HIV- infected individuals'results in increased anti-HIV T cell responses. Our preliminary studies of mechanism suggest that viral replication is associated with Treg accumulation in lymphoid tissues of HIV-infected patients. Importantly, similar Treg accumulation occurs in the lymphoid tissues of SIV-infected macaques, validating the SIV/macaque experimental system as a relevant model in which the functional role of tissue Treg can be studied. Our preliminary data also suggest that HIV-CD4 interactions cause such Treg accumulation by providing a survival signal to Treg. The aim of the current proposal is to define the mechanisms and consequences of Treg accumulation in lymphoid organs of HIV-infected donors. The underlying hypotheses are that: (a) the level of viral replication directly influences Treg accumulation in lymphoid tissues;(b) HIV itself causes this accumulation by promoting Treg survival and/or Treg expansion;and (c) Treg accumulation negatively affects T-cell mediated control of virus replication. To test these hypotheses, we aim to: (1) determine whether natural, as well as HAART-mediated, control of viral replication affects Treg accumulation in lymphoid tissues of HIV-infected individuals;(2) define the mechanisms underlying HIV-mediated Treg accumulation in lymphoid tissues, using the in vitro model of exposure of CD4+ T cells to HIV;and (3) determine the mechanistic role of Treg in regulating anti-viral T cell responses in the simian model of HIV.